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Patent Issued for Sustained Drug Delivery System

February 22, 2014



By a News Reporter-Staff News Editor at Obesity, Fitness & Wellness Week -- A patent by the inventors Abe, Toshiaki (Miyagi, JP); Nagai, Nobuhiro (Miyagi, JP); Kaji, Hirokazu (Miyagi, JP); Kawashima, Takeaki (Miyagi, JP); Nishizawa, Matsuhiko (Miyagi, JP); Nishida, Koji (Miyagi, JP), filed on February 16, 2012, was published online on February 4, 2014, according to news reporting originating from Alexandria, Virginia, by NewsRx correspondents (see also Tohoku University).

Patent number 8642066 is assigned to Tohoku University (Miyagi, JP).

The following quote was obtained by the news editors from the background information supplied by the inventors: "A drug delivery system (DDS) of the concept of 'feeding a minimum necessary drug to where the demand is when needed' has been devised as a means for more safely and effectively performing drug chemotherapy. A transdermal DDS for controlling the absorption of an antianginal drug, nitroglycerin, or an antihypertensive drug, clonidine, from the skin and oral DDS using osmotic pressure have been put to practical use as DDS preparations.

"Eye disease is generally treated by the instillation administration of a drug. However, some drugs are little transferred to the retina or the vitreous body by this method. It also needs to be considered that the attempt of systemic administration thereof such as intravenous administration may less easily result in transfer to a treatment site as they each approach the effective concentration, due to the blood-aqueous barrier or the blood-retinal barrier, or can cause systemic side effects. A method has recently been attempted for directly injecting a drug into the vitreous body; however, according to this method, the drug is dispersed immediately after injection and metabolized, and the amount of the drug transferred to the target site is several percent or less. Thus, there may be a method which involves injecting a high concentration of the drug; however, it poses a risk of producing side effects on normal intraocular tissue. There is also frequent administration as another method; however, it is not practical in view of the risk of infection and the inconvenience of the procedure.

"To solve these problems, a DDS for intraocular therapy has been devised which safely and slowly releases a drug into the eye.

"DDS and Implant for Intraocular Therapy

"For example, there is a surgical implant, Vitrasert (Bausch & Lomb) for delivering ganciclovir into the eye as a non-degradable DDS. This is a device for surgically implanting a drug reservoir-type implant in the vitreous body. It has a slow-release period of about 3 years. However, in some cases, it requires reoperation to remove the implanted implant, or, when causing side effects, takes long to address them; thus, it is a problem that the risk of infection and the physical burden of a patient are increased. The slowly released drug is dispersed and metabolized in the vitreous body; thus, it is doubtful whether the drug at a curative level reaches a target site.

"For example, a 'biodegradable scleral plug' is disclosed as a DDS for intraocular therapy (see Patent Literature 1). This is a DDS for which polylactic acid is processed into plug form, punctured into the sclera, and left in place. It is characterized in that a metallic scleral plug used for closing an opening formed by vitreous surgery is prepared using a biodegradable polymer and allowed to include a drug so that the drug is slowly released with the degradation of the polymer and the opening is also closed up due to cure. However, as in the above implant, because the drug is dispersed in the vitreous body, it is doubtful whether the drug at a curative level reaches a target site. In addition, there is a problem of the risk of infection and the physical burden due to the vitreous surgery.

"For example, an implant for subjecting a drug-coated core-like polycaprolactone to direct subretinal implantation is disclosed as a DDS for intraocular therapy (see Patent Literature 2). The direct subretinal implantation requires vitreous surgery. Considerable technique is also required for an operator in order to embed the implant in the fragile retinal tissue. The implant is likely to cause infection and nick the retina and highly invasive and therefore not practical.

"For example, 'a polymer delivery formulation for delivery to an optic portion' is discloses as a DDS for intraocular therapy (see Patent Literature 3). This is a method for intravitreally or subconjunctivally injecting microspheres consisting of lactide/glycolide copolymer, containing a drug using polyethylene glycol as a carrier solvent. However, even the use of such a fluid DDS carrier has a problem that it is easily dispersed to the periphery of a target site, reducing the local effect of the drug.

"As described above, these implants of the type of being implanted in the vitreous body are accompanied by the risk of infection and the physical and economic burden on the patient associated with operation. In addition, an advanced technique is required for an operator. Implant once implanted sometimes cannot be removed or exchanged when they have become unnecessary. Further, the drug dispersed in the vitreous body is metabolized and subjected to the control of substance permeation by the inner limiting membrane (ILM), the outer limiting membrane (OLM), and the blood-retinal barrier; thus, the amount of the drug reaching the retina and the choroid is estimated to be several percent or less, which may reduce the therapeutic effect thereof.

"To solve these problems, a less invasive transscleral DDS not requiring vitreous surgery using implantation on the scleral side is devised. The ability of by-passing the above-described ILM, OLM, and blood-retinal barrier by periocular drug delivery can increase the drug concentration in the retina compared to that for the intravitreal slow release, enables local delivery to posterior eye segment tissue, and can minimize side effects due to systemic administration. The sclera is easily permeated by a water-soluble substance, has reduced binding and adsorption of protease and protein, and has low cell density; thus, the drug readily permeates thereinto without receiving metabolism. For example, when albumin is intraocularly injected into the suprachoroid, it is known to be discharged outside the eye through the sclera (see Non Patent Literature 1). Examples of the transscleral DDS are as follows.

"For example, 'transscleral slow-release drug-targeted delivery to the retina and the choroid' is disclosed as a transscleral DDS (see Patent Literature 4). This uses a mechanical osmotic pump (ALZET, ALZA, Palo Alto, Calif.) as a DDS. The osmotic pump takes the form of being subcutaneously buried between the blade bones and transsclerally delivering a drug via a hose extending therefrom; however, the device is complicated and invasive because of implantation in the two areas of the blade bone and the sclera, which is not practical.

"For example, 'a non-invasive drug delivery system to posterior eye segment tissue using a gel-like composition' is disclosed as a transscleral DDS (see Patent Literature 5). This is a DDS for locally administering a drug to posterior eye segment tissue by administering a gel-like composition comprising the drug and a mucoadhesive substance to the eye surface. However, the gel-like composition is predicted to be readily dispersed to the periphery of an administration site after administration and becomes less effective because it comprises a water-soluble polymer component, and further has a problem that all of the gel-like composition cannot be recovered when it is made redundant.

"For example, 'an ophthalmologic drug-feeding device' is disclosed as a transscleral DDS (see Patent Literature 6). This is directed to provide an ophthalmic device which can be stably disposed in the eye, is comfortable, and has enough volume and mass to feed a drug for a long period of time. It is a device comprising a silicone elastomer having a curved surface and taper so as to fit on the sclera. The device itself is as large as 10 to 25 mm in width, 5 to 12 mm in height, and 1 to 3 mm in thickness. Its capability of slowly releasing a drug is not disclosed. The device is intended to be inserted into the anterior eye surface and not intended to release a drug to posterior eye segment tissue.

"For example, 'transscleral delivery' is disclosed as a transscleral DDS (see Patent Literature 7). This is a DDS intended for the delivery of rapamycin to posterior eye segment tissue. The subscleral injection of microspheres/nanoparticles, the scleral surface implantation of a biodegradable polymer as a thin layer membrane having an impervious lining, the implantation thereof in a surgically formed scleral pocket, the implantation of a solid core of drug in the scleral pocket, and the insertion of a silicone track delivery system into the recti tendon are disclosed as a delivery system. A method involving using a specially designed injector/inserting device and inhibiting the movement of DDS by employing a suture or attaching a fine needle to DDS itself in order to secure DDS is disclosed as an insertion method. An effective concentration of rapamycin is shown to permeate by preparing an in vitro scleral model in which a human donor sclera is mounted in a chamber to evaluate the permeability of rapamycin; however, the period of slow release is not clearly indicated.

"As described above, the transscleral DDSs previously reported have had a problem that they are complex systems, have fluidity, cause a feeling of a foreign body because of their large size, or have a short period of slow release.

"Collagen and polyethylene glycol (PEG) have conventionally been used as base materials for DDS. Collagen is a protein of biological origin and functions as an extracellular matrix in a living body to regulate the proliferation and differentiation of cells. Due to such biological properties, it is used as a biomaterial for tissue engineering or regenerative medicine. More recently, it is clinically applied to an injectable filler, a hemostatic agent, an artificial skin, or the like. PEG is a biocompatible synthetic polymer which is nontoxic and exhibits reduced interaction with a living body. It is also subjected to clinical applications in the medical field, including the stabilization of a protein drug in a living body by pegylation such as use as an emulsifier for cosmetics. Examples of materials for treating the eye using collagen and PEG are as follows.

"For example, 'a suspension for treating the eye' is disclosed as a material for treating the eye using collagen (see Patent Literature 8). This is directed to provide an artificial tear solution for preventing the drying of the eye surface, and comprises a mixture of biodegradable particles (collagen, gelatin, etc.) 0.5 mm in diameter, an ophthalmologic drug, and a lipid-like substance; it is intended for treating the eye surface and is not a DDS intended for intraocular therapy.

"For example, 'an injectable collagen-based drug delivery preparation and its use' is disclosed as a material for treating the eye using collagen (see Patent Literature 9). This is directed to provide a subcutaneous injection-type drug delivery carrier, and is a DDS in which a mixture of atelocollagen, a drug, and a cross-linking agent is subcutaneously injected and then cross-linked in situ for solidification. The target disease therefor is not described. However, the in situ cross-linking is unfavorable because the unreacted cross-linking agent may induce an inflammatory response in the biotissue.

"For example, 'an optically clear ultraviolet-absorbing biocompatible polymer material using collagen as a base material and a method for producing the same' is disclosed as a material for treating the eye using collagen (see Patent Literature 10). This is intended for producing an intraocular lens and a contact lens, and a hydrophilic or hydrophobic acrylic monomer and allyl monomer are graft-polymerized with collagen in order to obtain transparency and ultraviolet absorptivity. A material comprising a composite of collagen and PEG is exemplified; it is not intended for intraocular therapy because it is not packed with a drug.

"For example, 'a collagen gel and a method for producing the same' is disclosed as a DDS using collagen (see Patent Literature 11). This describes a method for producing a collagen gel, which involves mixing a cross-linking agent in the process of fiber formation of collagen and causing the fiber formation and the cross-linking to occur simultaneously. A DDS is disclosed which uses a dry collagen sheet obtained by removing a solvent in the collagen gel; however, examples thereof are not described and the slow-releasing capability and use thereof are unknown.

"As described above, for a material for treating the eye using collagen, a transscleral DDS is not disclosed which is intended for drug delivery to posterior eye segment tissue.

"For example, 'an injection for intraocular tissue comprising a drug-polyethylene glycol conjugate' is disclosed as a material for treating the eye using PEG (see Patent Literature 12). The injection exploits the failure of the drug conjugated to PEG to transfer to the systemic circulation when directly injected into the eye because it has a larger apparent molecular weight, and is intended for the intraocular stabilization of the drug by PEG. However, it depends on the dispersion of the intraocularly injected drug whether the drug is transferred to a target site, and, as described above, the drug suffers from permeation inhibition by the ILM, OLM, and blood-retinal barrier; thus, the arrival rate of the drug at posterior eye segment tissue is several percent or less, posing a problem that the therapeutic effect thereof is decreased.

"For example, 'an ophthalmic drug delivery system using polymer micelles' is disclosed as a material for treating the eye using PEG (see Patent Literature 13). This is a method which involves including a light-sensitive substance used for photodynamic therapy (PDT) in micelles each using PEG as an outer shell and polyaspartic acid (Asp) as an inner shell and using the resultant for PDT. The use of this method enables the effective delivery of the light-sensitive substance to the posterior eye segment tissue producing vascularization and can block the vascularization using a low level of laser irradiation. However, depending on the disease state, it is necessary to repeatedly maintain the laser irradiation, posing a problem of side effects of the laser irradiation on the eye tissue.

"As described above, for a material for treating the eye using PEG, a transscleral DDS is not disclosed which is intended for drug delivery to posterior eye segment tissue."

In addition to the background information obtained for this patent, NewsRx journalists also obtained the inventors' summary information for this patent: "Although DDS is intended for 'feeding a minimum necessary drug to where the demand is when needed', the site of the implantation thereof has been limited by the inadequate shape/size of DDS, posing a problem that the drug reaches a non-target site to cause side effects. The use of DDS has also sometimes been accompanied by an inflammatory response derived from the base material of DDS. In addition, some conventional DDSs have produced the initial burst to initially release an excessive amount of a drug or have had an insufficient period of slow release.

"For a DDS for treating eye disease, a method is disclosed which involves surgically administrating/implanting a DDS carrier and a drug through the vitreous body to the subretina; however, this method places a heavy physical/economic burden on patients, also poses a high risk of infection, and sometimes requires an operator to have an advanced technique. The DDS carrier thus administered is most often difficult to remove when it is made redundant or when it produces side effects. As a method for solving this problem, some transscleral DDSs are disclosed; however, they have had a problem that they are complex systems, have fluidity, cause a feeling of a foreign body because of their large size, or have a short period of slow release.

"An object of the present invention is to provide a DDS for solving the above problems, which can be safely and simply implanted into the eye and can deliver a drug into the eye over a long period of time without the initial burst, particularly in application to the treatment of eye disease. Another object thereof is to provide a highly versatile long-term slow-release DDS also capable of being applied to organs/tissues other than the eye.

"As described above, the DDSs previously disclosed have had a problem that it is inappropriate in the biocompatibility and shape, cannot achieve stable drug release due to the production of the initial burst, or has a short period of slow release. Particularly, the DDSs for intraocular therapy have had a problem that they are complex systems, have fluidity, cause a feeling of a foreign body because of their large size, or have a short period of slow release.

"To solve these problems, the present inventors have made extensive studies, aiming at development of a compact-size stepwise slow-releasing transscleral DDS capable of unidirectionally delivering a therapeutic level of a drug to the choroid and the retina for a long period of time without damage to tissue.

"The present inventors have used collagen and PEG as base materials for DDS. The present inventors have developed a drug reservoir capsule 1 mm or less in thickness and 1 cm.sup.2 or less in area to facilitate insertion into the sclera (the sclera as used herein refers to the range from above the choroid to under the conjunctiva, that is, the subsclera, the inside of the sclera, the episclera, the subconjunctiva, and the suprachoroid). The capsule has been produced by capping a box-shaped reservoir prepared from PEG with a porous PEG sheet. The porous PEG sheet has been produced by collagenase digestion using collagen particles as a porogen (a porous mold). The change of the mixing amount of collagen particles can change the pore density. As a result, it has been found that the permeability/slow-release capability of a drug in the capsule can be easily controlled. In addition, it has been found that the drug can be packed in the capsule not in the form of a common solution but in the form of the drug impregnated in collagen (the form of collagen may be a gel or particles) or the resultant collagen wrapped in PEG and pelletized to promote slow release. In other words, this is a new DDS concept of 2 step slow release according to which the slow release of the drug from the collagen occurs in the capsule and the drug is further slowly released through the porous sheet. The combination of the method for packing the drug in the capsule and the porosity of the porous PEG sheet has enabled the period of slow release of 5 years or more to be achieved. In addition, it has been found that the inside of a capsule can be compartmented using a fine processing technology to pack several drugs and the change of the packing form enables the slow release of several drugs at different speeds. Animal experiments have showed that a drug is slowly released in a sustained manner from the device implanted on the sclera.

"Thus, a scleral DDS has been developed which can slowly release a drug for a longer period of time than that for a conventional technique, is easily inserted into the sclera, and can slowly release several drugs at different speeds, thereby accomplishing the present invention.

"Thus, the present invention is as follows.

"[1] A sustained drug delivery system in which an implant is implanted in the body, wherein the implant is a polyethylene glycol (PEG) capsule having a structure in which a box-shaped PEG internally containing a collagen impregnated with a therapeutic drug or a PEG pellet including the collagen impregnated with a therapeutic drug is capped with a porous PEG sheet and the internal drug is slowly released through the porous PEG sheet. [2] The sustained drug delivery system according to [1], wherein the system is a stepwise slow-releasing drug delivery system in which the collagen impregnated with a therapeutic drug or the PEG pellet including the collagen impregnated with a therapeutic drug is internally contained in the box-shaped PEG. [3] The sustained drug delivery system according to [1] or [2], wherein the therapeutic drug is in the form of a solution, powdered particles, or a mixture thereof. [4] The sustained drug delivery system according to any of [1] to [3], wherein the collagen impregnated with a therapeutic drug is in the form of a collagen gel or collagen particles. [5] The sustained drug delivery system according to any of [1] to [4], wherein the PEG pellet in which the collagen impregnated with a therapeutic drug is embedded is prepared by mixing the collagen impregnated with a drug, a photo-curable polyethylene glycol, and a photopolymerization initiator and curing the mixture. [6] The sustained drug delivery system according to any of [1] to [5], wherein the box-shaped PEG is prepared by mixing a photo-curable polyethylene glycol and a photopolymerization initiator and curing the mixture with UV light. [7] The sustained drug delivery system according to any of [1] to [6], wherein the porous PEG sheet is prepared by a photo-curable polyethylene glycol solution, collagen particles, and a photopolymerization initiator, irradiating the mixture with UV light for curing, and then digesting the collagen particles. [8] The sustained drug delivery system according to any of [5] to [7], wherein the photo-curable polyethylene glycol is selected from the group consisting of polyethylene glycol dimethacrylate (PEGDM), polyethylene glycol methacrylate (PEGMA), and polyethylene glycol diacrylate (PEGDA). [9] The sustained drug delivery system according to any of [1] to [8], wherein the system is a sustained drug delivery system for treating eye disease in which an implant for administering a drug for treating eye disease in a sustained manner is implanted in a portion from above the choroid to under the conjunctiva, that is, the subsclera, the inside of the sclera, the episclera, the subconjunctiva, and the suprachoroid. [10] The sustained drug delivery system according to [9], wherein the eye disease is a disease in which multiple factors including a gene and an environmental factor are involved, a retinal blood vessel lesion, or a disease in which inflammation or damage spreads to the choroid/retina/vitreous body. [11] The sustained drug delivery system according to [10], wherein the disease in which multiple factors including a gene and an environmental factor are involved is selected from the group consisting of retinal pigmentary degeneration, age-related macular degeneration, and glaucoma; the retinal blood vessel lesion is selected from the group consisting of retinal artery occlusion, branch retinal vein occlusion, and diabetic retinopathy; and the disease in which inflammation or damage spreads to the choroid/retina/vitreous body is uveitis. [12] The sustained drug delivery system according to any of [1] to [11], wherein the therapeutic drug is selected from the group consisting of a drug suppressing vascularization, a drug promoting the growth of nerve cells, a steroid drug, a therapeutic drug for glaucoma, an anti-inflammatory drug, an antifungal drug, and an anticancer drug. [13] A drug slow-releasing implant, wherein the implant is a PEG capsule having a structure in which a box-shaped PEG internally containing a therapeutic drug, a collagen impregnated with the therapeutic drug, or a PEG pellet in which the collagen impregnated with the therapeutic drug is embedded is capped with a porous PEG sheet and the internal drug is slowly released through the porous PEG sheet. [14] The drug slow-releasing implant according to [13], wherein the implant is a stepwise slow-releasing implant in which the collagen impregnated with the therapeutic drug or the PEG pellet in which the collagen impregnated with the therapeutic drug is embedded is internally contained in the box-shaped PEG. [15] The drug slow-releasing implant according to [13] or [14], wherein the therapeutic drug for impregnation is in the form of a solution, powdered particles, or a mixture thereof. [16] The drug slow-releasing implant according to any of [13] to [15], wherein the collagen impregnated with the therapeutic drug is in the form of a collagen gel or collagen particles. [17] The drug slow-releasing implant according to any of [13] to [16], wherein the PEG pellet in which the collagen impregnated with the therapeutic drug is embedded is prepared by mixing the collagen impregnated with the drug, a photo-curable polyethylene glycol, and a photopolymerization initiator and curing the mixture with UV light. [18] The drug slow-releasing implant according to any of [13] to [17], wherein the box-shaped PEG is prepared by mixing a photo-curable polyethylene glycol and a photopolymerization initiator and curing the mixture with UV light. [19] The drug slow-releasing implant according to any of [13] to [18], wherein the porous PEG sheet is prepared by mixing a photo-curable polyethylene glycol solution, collagen particles, and a photopolymerization initiator, irradiating the mixture with UV light for curing, and then digesting the collagen particles. [20] The drug slow-releasing implant according to any of [17] to [19], wherein the photo-curable polyethylene glycol is selected from the group consisting of polyethylene glycol dimethacrylate (PEGDM), polyethylene glycol methacrylate (PEGMA), and polyethylene glycol diacrylate (PEGDA). [21] The drug slow-releasing implant according to any of [13] to [20], wherein the implant is for treating eye disease and implanted in the sclera that is a portion from above the choroid to under the conjunctiva, that is, the subsclera, the inside of the sclera, the episclera, the subconjunctiva, and the suprachoroid. [22] The drug slow-releasing implant according to [21], wherein the eye disease is a disease in which multiple factors including a gene and an environmental factor are involved, a retinal blood vessel lesion, or a disease in which inflammation or damage spreads to the choroid/retina/vitreous body. [23] The drug slow-releasing implant according to [22], wherein the disease in which multiple factors including a gene and an environmental factor are involved is selected from the group consisting of retinal pigmentary degeneration, age-related macular degeneration, and glaucoma; the retinal blood vessel lesion is selected from the group consisting of retinal artery occlusion, branch retinal vein occlusion, and diabetic retinopathy; and the disease in which inflammation or damage spreads to the choroid/retina/vitreous body is uveitis. [24] The drug slow-releasing implant according to any of [14] to [23], wherein it is selected from the group consisting of a drug suppressing vascularization, a drug promoting the growth of nerve cells, a drug promoting vascularization, a steroid drug, a therapeutic drug for glaucoma, an anti-inflammatory drug, an antifungal drug, and an anticancer drug.

"The present specification encompasses the contents of the specification and/or drawings of Japanese Patent Application No. 2009-189462 on which the priority of the present application is based."

URL and more information on this patent, see: Abe, Toshiaki; Nagai, Nobuhiro; Kaji, Hirokazu; Kawashima, Takeaki; Nishizawa, Matsuhiko; Nishida, Koji. Sustained Drug Delivery System. U.S. Patent Number 8642066, filed February 16, 2012, and published online on February 4, 2014. Patent URL: http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&p=91&u=%2Fnetahtml%2FPTO%2Fsearch-bool.html&r=4538&f=G&l=50&co1=AND&d=PTXT&s1=20140204.PD.&OS=ISD/20140204&RS=ISD/20140204

Keywords for this news article include: Alkenes, Therapy, Polyenes, Treatment, Hydrocarbons, Organic Chemicals, Tohoku University, Polyethylene Glycols, Drug Delivery Systems, Extracellular Matrix Proteins.

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